The essential role of Btk in autoimmune disease is underlined by the observations that Btk-deficient mice are protected in standard preclinical models for rheumatoid arthritis (Jansson and Holmdahl, 1993), systemic lupus erythematosus (Steinberg, B. J. et al., J. Clin. Invest, 70, 587-597, 1982), as well as allergic disease and anaphylaxis (Hata, D. et al., J. Exp. Med. 187, 1235-1247, 1998). In addition, many cancers and lymphomas express Btk and appear to be dependent on Btk function (Davis, R. E. et al., Nature, 463, 88-92, 2010).
Therefore, inhibition of Btk activity may be useful in the treatment of immune disorders such as rheumatoid arthritis, systemic lupus erythematosus, allergic diseases, anaphylaxis and inflammatory conditions. Moreover, inhibition of Btk may be useful in the treatment of cancers of haematopoietic origin including chronic myelogenous leukemia, myeloid leukemia, non-Hodgkin lymphoma and other B cell lymphomas.
The compounds of the present invention may therefore potentially be useful in the treatment of a wide range of disorders, particularly Btk-related diseases or disorders, and may for example be useful in the treatment of autoimmune disorders, inflammatory diseases, allergic diseases, airway diseases, such as asthma and chronic obstructive pulmonary disease (COPD), transplant rejection, or cancers e.g. of hematopoietic origin or solid tumors.
More particularly, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof;
wherein,R1 is hydrogen, C1-C6 alkyl optionally substituted by hydroxy;R2 is hydrogen or halogen;R3 is hydrogen or halogen;R4 is hydrogen,R5 is phenyl optionally substituted by halogen; SF5; NR6R7; hydroxy; C1-C6 alkoxy; C1-C6 alkenyl; C1-C6 alkyl carbonyl; C1-C6 alkyl optionally substituted by hydroxy, halogen, or C1-C6 alkoxy; or C3-C6 cycloalkyl optionally substituted by halogen, hydroxy, or C1-C6 alkyl optionally substituted by halogen; orR5 is a 4-14 membered mono- or bicyclic heterocyclyl or heteroaryl ring system comprising 1, 2 or 3 heteroatoms selected from N, S and O that ring being optionally substituted by halogen; hydroxy; C1-C6 alkoxy optionally substituted by hydroxy or halogen; or C1-C6 alkyl optionally substituted by hydroxy or halogen;or R4 and R5 together with the atoms to which they are bound form a piperidone ring, optionally comprising an annulated phenyl ring, any such ring being optionally substituted by C1-C6 alkyl, C1-C6 alkoxy, or C3-C6 cycloalkyl each of which substitution member may optionally be substituted by halogen or hydroxy;R6 and R7 are independently selected from hydrogen or C1-C6 alkyl;or R6 and R7 together with the nitrogen atom to which they are bound form a 4-8 membered saturated azacycloalkane ring, optionally substituted by halogen, hydroxy or C1-C6 alkyl;X is O, S(O)n wherein n is 0, 1 or 2, or
wherein q is 2 or 3, and R10 is absent;or X is CH or N; and R10 is hydrogen, hydroxy, —NR6R7, —CO—R11, —S(O)p—R12 whereinp is 1 or 2,R 11 is C1-C6 alkyl optionally substituted by hydroxy, cyano, halogen, carboxy or C1-C6 alkoxy carbonyloxy; or NR6R7; andR12 is C1-C6 alkyl or NR6R7.
In another embodiment the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof wherein R1 is hydrogen, methyl or hydroxymethyl, R2 and R3 are independently hydrogen or fluoro, R4 is hydrogen, R5 is phenyl substituted by halogen; C1-C6 alkoxy or C1-C6 alkyl optionally substituted by halogen or hydroxy; or C3-C6 cycloalkyl optionally substituted by halogen, hydroxy, C1-C6 alkyl optionally substituted by halogen; X is O, S(O), wherein n is 0, 1 or 2, or
wherein q is 2 or 3, and R10 is absent;and the remaining variables are as defined above.
In another embodiment the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof wherein R1 is hydrogen, methyl or hydroxymethyl, R2 and R3 are independently hydrogen or fluoro, R4 together with R5 is a 3,4-dihydro-2H-isoquinolin-1-one optionally substituted by C3-C6 cycloalkyl or C1-C6 alkyl optionally substituted by hydroxy; X is O, S(O), wherein n is 0, 1 or 2, or
wherein q is 2 or 3, and R10 is absent; and the remaining variables are as defined above.
In another embodiment the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof wherein R1 is hydrogen, methyl or hydroxymethyl, R2 and R3 are independently hydrogen or fluoro, R4 is hydrogen, R5 is phenyl substituted by halogen; C1-C6 alkoxy; C1-C6 alkyl optionally substituted by halogen or hydroxy; or C3-C6 cycloalkyl optionally substituted by halogen, hydroxy, or C1-C6 alkyl optionally substituted by halogen; X stands for O and R10 is absent; or X stands for N, and R10 is hydrogen or —CO—R11, and the remaining variables are as defined above.
In another embodiment the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof wherein R1 is hydrogen, methyl or hydroxymethyl, R2 and R3 are independently hydrogen or fluoro, R4 is hydrogen; R5 is phenyl substituted by C1-C6 alkoxy; C1-C6 alkyl optionally substituted by halogen or hydroxy; or C3-C6 cycloalkyl optionally substituted by halogen, hydroxy, or C1-C6 alkyl optionally substituted by halogen; X stands for N, R10 is hydrogen or —CO—R11, R11 stands for NR6R7 wherein R6 and R7 are independently hydrogen or methyl; and the remaining variables are as defined above.
In another embodiment the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof wherein R1 is hydrogen, methyl or hydroxymethyl, R2 and R3 are independently hydrogen or fluoro, R4 is hydrogen, R5 is azetidine optionally substituted by C1-C6 alkoxy, X stands for N, and R10 is hydrogen or —CO—R11, and the remaining variables are as defined above.
In another embodiment the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof wherein R1 is hydrogen, methyl or hydroxymethyl, R2 and R3 are independently hydrogen or fluoro, R4 together with R5 is a 3,4-dihydro-2H-isoquinolin-1-one optionally substituted by C3-C6 cycloalkyl or C1-C6 alkyl optionally substituted by hydroxy, X stands for N, and R10 is hydrogen or —CO—R11, and the remaining variables are as defined above.
In another embodiment the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof wherein R1 is hydrogen, methyl or hydroxymethyl, R2 and R3 are independently hydrogen or fluoro, R4 together with R5 is a 3,4-dihydro-2H-isoquinolin-1-one substituted by C3-C6 cycloalkyl or C1-C6 alkyl optionally substituted by hydroxy in the 6-position of said isoquinolin-ring, X stands for N, and R10 is hydrogen or —CO—R11, and the remaining variables are as defined above.
In another embodiment the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof wherein R1 is hydrogen, methyl or hydroxymethyl, R2 and R3 are independently hydrogen or fluoro, R4 is hydrogen, R5 is azetidine optionally substituted by C1-C6 alkoxy, X stands for 0, and the remaining variables are as defined above.
In another embodiment the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof wherein R1 is hydrogen, methyl or hydroxymethyl, R2 and R3 are independently hydrogen or fluoro, R4 together with R5 is a 3,4-dihydro-2H-isoquinolin-1-one optionally substituted by C3-C6 cycloalkyl or C1-C6 alkyl optionally substituted by hydroxy, X stands for 0, and the remaining variables are as defined above.
In another embodiment the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof wherein R1 is hydrogen, methyl or hydroxymethyl, R2 and R3 are independently hydrogen or fluoro, R4 together with R5 is a 3,4-dihydro-2H-isoquinolin-1-one substituted by C3-C6 cycloalkyl or C1-C6 alkyl optionally substituted by hydroxy in the 6-position of said isoquinolin-ring, X stands for 0, and the remaining variables are as defined above.
In another embodiment the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof wherein R1 is hydrogen, methyl or hydroxymethyl, R2 and R3 are independently from each other selected from hydrogen and halogen, R4 is hydrogen, R5 is phenyl substituted one or more times by halogen, C3-C6 cycloalkyl, or C1-C6 alkyl optionally substituted by hydroxy, X stands for O or S, and R10 is absent.
In another embodiment the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof wherein R1 is methyl or hydroxymethyl, R2 and R3 are independently from each other selected from hydrogen and halogen, R4 is hydrogen, R5 is phenyl substituted one or more times by halogen, C3-C6 cycloalkyl, or C1-C6 alkyl optionally substituted by hydroxy, X stands for N, R10 is hydrogen or —CO—R11, and R11 is NR6R7 wherein R6 and R7 are independently selected from C1-C6-alkyl.
With regard to a compound of formula (I) the following significances represent further embodiments of the invention independently, collectively or in any combination or in any sub-combination thereof:                1. R1 is hydrogen, methyl or hydroxymethyl;        2. R1 is methyl or hydroxymethyl;        3. R2 and R3 are independently hydrogen or fluoro;        4. R1 is methyl or hydroxymethyl and R2 and R3 are independently hydrogen or fluoro;        5. R4 is hydrogen;        6. R4 together with R5 is a 3,4-dihydro-2H-isoquinolin-1-one optionally substituted by C3-C6 cycloalkyl or C1-C6 alkyl optionally substituted by hydroxy;        7. R4 together with R5 is a 3,4-dihydro-2H-isoquinolin-1-one optionally substituted by C3-C6 cycloalkyl or C1-C6 alkyl optionally substituted by hydroxy in the 6-position of the 3,4-dihydro-2H-isoquinolin-1-one ring;        8. R5 is phenyl optionally substituted by —NR6R7, halogen; C1-C6 alkoxy, C1-C6 alkenyl, C3-C6 cycloalkyl, or C1-C6 alkyl optionally substituted by halogen or hydroxy;        9. R5 is phenyl substituted by —NR6R7, halogen, C1-C6 alkoxy or C1-C6 alkyl optionally substituted by halogen or hydroxy;        10. R5 is phenyl substituted by halogen, C1-C6 alkoxy, C3-C6 cycloalkyl or C1-C6 alkyl optionally substituted by fluoro or hydroxy;        11. R5 is a 4-, 5-, 6-, or 7-membered monocyclic heterocycle, or a 7-, 8-, 9-, 10-, 11-, or 12-membered bicyclic heterocycle comprising 1, 2 or 3 heteroatoms selected from N, S and O that ring being optionally substituted by halogen; hydroxy; C1-C6 alkoxy optionally substituted by hydroxy or halogen; or C1-C6 alkyl optionally substituted by hydroxy or halogen;        12. R5 is a 4-, 5-, 6-, or 7-membered monocyclic heterocycle comprising 1 or 2 heteroatoms selected from N, S and O that ring being optionally substituted by halogen; hydroxy; C1-C6 alkoxy optionally substituted by hydroxy or halogen; or C1-C6 alkyl optionally substituted by hydroxy or halogen;        13. R5 is azetidine substituted by C1-C6 alkoxy or C1-C6 alkyl;        14. X is O and R10 is absent or is N and R10 is H or CO—R11;        15. X is O and R10 is absent or is N and R10 is CO—R11;        16. X is O and R10 is absent;        17. X is N and R10 is CO—R11;        18. R11 is NR6R7 and R6 and R7 are independently selected from hydrogen or C1-C6 alkyl;        19. R11 is NR6R7 and R6 and R7 are independently selected from C1-C6 alkyl;        20. R11 is NR6R7 and R6 and R7 are independently selected from C1-C3 alkyl;        21. R11 is NR6R7 and R6 and R7 are methyl.        
In another embodiment the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use as a medicament.
In another embodiment the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of a disease or disorder mediated by Btk.
In another embodiment the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, which is selected from:    4-(4-{5-Fluoro-3-[4-(1-fluoro-cyclopropyl)-benzoylamino]-2-methyl-phenyl}-7H-pyrrolo[2′3-d]pyrimidin-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid dimethylamide,    4-(4-{3-[(3,3-Dimethyl-2,3-dihydro-benzofuran-6-carbonyl)-amino]-5-fluoro-2-methyl-phenyl}-7H-pyrrolo[2′3-d]pyrimidin-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid dimethylamide,    4-(4-{5-Fluoro-2-methyl-3-[(5-methyl-4,5,6,7-tetrahydro-benzo[b]thiophene-2-carbonyl)-amino]-phenyl}-7H-pyrrolo[2′3-d]pyrimidin-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid dimethylamide,    4-(4-{5-Fluoro-3-[4-isopropyl-methyl-amino)-benzoylamino]-2-methyl-phenyl}-7H-pyrrolo[2′3-d]pyrimidin-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid dimethylamide,    3-Methyl-1H-indole-6-carboxylic acid {3-[6-(1-dimethylcarbamoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-5-fluoro-2-methyl-phenyl}-amide,    4-(4-{5-Fluoro-3-[4-(2-hydroxy-1,1-dimethyl-ethyl)-benzoylamino]-2-methyl-phenyl}-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid dimethylamide,    4-{4-[5-Fluoro-2-methyl-3-(4-piperidin-1-yl-benzoylamino)-phenyl]-7H-pyrrolo[2,3-d]pyrimidin-6-yl}-3,6-dihydro-2H-pyridine-1-carboxylic acid dimethylamide,    4-{4-[5-Fluoro-3-(isopropenyl-benzoylamino)-2-methyl-phenyl]-7H-pyrrolo[2,3-d]pyrimidin-6-yl}-3,6-dihydro-2H-pyridine-1-carboxylic acid dimethylamide,    4-(4-{5-Fluoro-2-methyl-3-[4-(1-trifluoromethyl-cyclopropyl)-benzoylamino]-phenyl}-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid dimethylamide,    4-{4-[5-Fluoro-3-(4-isopropoxy-benzoylamino)-2-methyl-phenyl]-7H-pyrrolo[2,3-d]pyrimidin-6-yl}-3,6-dihydro-2H-pyridine-1-carboxylic acid dimethylamide,    4-(4-{5-Fluoro-3-[4-pentafluorothio-benzoylamino]-2-methyl-phenyl}-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid dimethylamide,    4-(4-{5-Fluoro-3-[4-(2-methoxy-1,1-dimethyl-ethyl)-benzoylamino]-2-methyl-phenyl}-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid dimethylamide,    4-(4-{5-Fluoro-3-[4-(1-methoxy-1-methyl-ethyl)-benzoylamino]-2-methyl-phenyl}-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid dimethylamide,    1-Methyl-1H-pyrrolo[2,3-b]pyridine-6-carboxylic acid {3-[6-(1-dimethyl-carbamoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-5-fluoro-2-methyl-phenyl}-amide,    4-{4-[3-(4-Dimethylamino-benzoylamino)-5-fluoro-2-methyl-phenyl]-7H-pyrrolo[2,3-d]pyrimidin-6-yl}-3,6-dihydro-2H-pyridine-1-carboxylic acid dimethylamide,    4-(4-{3-[2-Fluoro-4-(1-hydroxy-1-methyl-ethyl)-benzoylamino]-2-hydroxymethyl-phenyl}-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid dimethylamide,    4-{4-[3-(4-Cyclopropyl-benzoylamino)-2-hydroxymethyl-phenyl]-7H-pyrrolo[2,3-d]pyrimidin-6-yl}-3,6-dihydro-2H-pyridine-1-carboxylic acid dimethylamide,    4-(4-{5-Fluoro-2-methyl-3-[4-(2,2,2-trifluoro-1-hydroxy-1-methyl-ethyl)-benzoylamino]-phenyl}-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid dimethylamide,    4-{4-[3-(4-Acetyl-benzoylamino)-5-fluoro-2-methyl-phenyl]-7H-pyrrolo[2,3-d]pyrimidin-6-yl}-3,6-dihydro-2H-pyridine-1-carboxylic acid dimethylamide,    4-{4-[3-(4-Cyclopropyl-benzoylamino)-4-fluoro-phenyl]-7H-pyrrolo[2,3-d]pyrimidin-6-yl}-3,6-dihydro-2H-pyridine-1-carboxylic acid dimethylamide,    4-(4-{4-Fluoro-3-[4-(2-hydroxy-1,1-dimethyl-ethyl)-benzoylamino]-phenyl}-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid dimethylamide,    N-{3-[6-(3,6-Dihydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-5-fluoro-2-methyl-phenyl}-2-fluoro-4-(1-hydroxy-1-methyl-ethyl)-benzamide,    N-{3-[6-(3,6-Dihydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-2-hydroxymethyl-phenyl}-2-fluoro-4-(1-hydroxy-1-methyl-ethyl)-benzamide,    4-tert-Butyl-N-{3-[6-(3,6-dihydro-2H-thiopyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-5-fluoro-2-methyl-phenyl}-benzamide,    4-tert-Butyl-N-{5-fluoro-2-methyl-3-[6-(3,6-dihydro-1-oxido-2H-thiopyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-phenyl}-benzamide,    4-tert-Butyl-N-{3-[6-(3,6-dihydro-1,1-dioxido-2H-thiopyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-5-fluoro-2-methyl-phenyl}-benzamide,    4-tert-Butyl-N-{3-[6-(1,4-dioxa-spiro[4.5]dec-7-en-8-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-5-fluoro-2-methyl-phenyl}-benzamide,    4-tert-Butyl-N-{5-fluoro-3-[6-(4-hydroxy-cyclohex-1-enyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-2-methyl-phenyl}-benzamide,    4-{4-[3-(4-Cyclopropyl-benzoylamino)-5-fluoro-2-methyl-phenyl]-7H-pyrrolo[2′3-d]pyrimidin-6-yl}-3,6-dihydro-2H-pyridine-1-carboxylic acid dimethylamide,    4-Cyclopropyl-N-(5-fluoro-2-methyl-3-{6-[1-(pyrrolidine-1-carbonyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}-phenyl)-benzamide,    Acetic acid 2-(4-{4-[3-(4-cyclopropyl-benzoylamino)-5-fluoro-2-methyl-phenyl]-7H-pyrrolo[2,3-d]pyrimidin-6-yl}-3,6-dihydro-2H-pyridin-1-yl)-2-oxo-ethyl ester,    4-Cyclopropyl-N-(5-fluoro-3-{6-[1-(2-hydroxy-actyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}-2-methyl-phenyl)benzamide,    N-(3-{6-[1-(2-Cyano-acetyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}-5-fluoro-2-methyl-phenyl)-4-cyclopropyl-benzamide,    N-(5-Fluoro-2-methyl-3-{6-[1-(pyrrolidine-1-carbonyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}-phenyl)-4-(pentafluoro-sulfanyl)-benzamide,    Acetic acid 2-[4-(4-{5-fluoro-2-methyl-3-[4-(pentafluoro-sulfanyl)-benzoylamino]-phenyl}-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3,6-dihydro-2H-pyridin-1-yl]-2-oxo-ethyl ester,    N-(5-Fluoro-3-{6-[1-(2-hydroxy-acetyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}-2-methyl-phenyl)-4-(pentafluoro-sulfanyl)-benzamide,    4-{4-[3-(4-tert-Butyl-benzoylamino)-2-(tert-butyl-diphenyl-silanyloxymethyl)-phenyl]-7H-pyrrolo[2,3-d]pyrimidin-6-yl}-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester,    4-tert-Butyl-N-(3-{6-[1-(2-fluoro-acetyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}-2-hydroxymethyl-phenyl)-benzamide,    4-(4-{5-Fluoro-3-[2-fluoro-4-(1-hydroxy-1-methyl-ethyl)-benzoylamino]-2-methyl-phenyl}-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid dimethylamide,    4-tert-Butyl-N-{5-fluoro-2-methyl-3-[6-(1,2,3,6-tetrahydro-pyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-phenyl}-benzamide,    4-{4-[3-(4-tert-Butyl-benzoylamino)-5-fluoro-2-methyl-phenyl]-7H-pyrrolo[2,3-d]pyrimidin-6-yl}-3,6-dihydro-2H-pyridine-1-carboxylic acid dimethylamide,    4-tert-Butyl-N-{5-fluoro-3-[6-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-2-methyl-phenyl}-benzamide,    4-tert-Butyl-N-{3-[6-(1-dimethylsulfamoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-5-fluoro-2-methyl-phenyl}-benzamide,    4-tert-Butyl-N-{3-[6-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-2-methyl-phenyl}-benzamide,    4-{4-[3-(6-tert-Butyl-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxymethyl-phenyl]-7H-pyrrolo[2,3-d]pyrimidin-6-yl}-3,6-dihydro-2H-pyridine-1-carboxylic acid dimethylamide,    4-{4-[3-(6-Cyclopropyl-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxymethyl-phenyl]-7H-pyrrolo[2,3-d]pyrimidin-6-yl}-3,6-dihydro-2H-pyridine-1-carboxylic acid dimethylamide,    4-(4-{2-Hydroxymethyl-3-[6-(1-hydroxy-1-methyl-ethyl)-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-phenyl}-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid dimethylamide,    4-tert-Butyl-N-{3-[6-(3,6-dihydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-2-hydroxymethyl-phenyl}-benzamide,    4-tert-Butyl-N-{3-[6-(3,6-dihydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-5-fluoro-2-methyl-phenyl}-benzamide,    N-{3-[6-(3,6-Dihydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-5-fluoro-2-methyl-phenyl}-4-dimethylamino-benzamide,    4-tert-Butyl-N-{3-[6-(3,6-dihydro-2H-thiopyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-2-methyl-phenyl}-benzamide,    4-tert-Butyl-N-{2-methyl-3-[6-(3,6-dihydro-1-oxido-2H-thiopyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-phenyl}-benzamide,    4-tert-Butyl-N-{3-[6-(3,6-dihydro-1,1-dioxido-2H-thiopyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-2-methyl-phenyl}-benzamide,    4-tert-Butyl-N-{3-[6-(1,4-dioxa-spiro[4.5]dec-7-en-8-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-2-hydroxymethyl-phenyl}-benzamide,    4-tert-Butyl-N-{3-[6-(4-hydroxy-cyclohex-1-enyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-2-hydroxymethyl-phenyl}-benzamide,    4-tert-Butyl-N-{3-[6-(4-dimethylamino-cyclohex-1-enyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-2-hydroxymethyl-phenyl}-benzamide,    4-(4-{3-[(3-tert-Butoxy-azetidine-1-carbonyl)-amino]-5-fluoro-2-methyl-phenyl}-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid dimethylamide,    4-(4-{5-Fluoro-3-[(3-isopropoxy-azetidine-1-carbonyl)-amino]-2-methyl-phenyl}-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid dimethylamide,    5-Fluoro-1,3-dihydro-isoindole-2-carboxylic acid {3-[6-(1-dimethylcarbamoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-5-fluoro-2-methyl-phenyl}-amide,    4-[4-(5-Fluoro-2-methyl-3-{[3-(2,2,2-trifluoro-1-trifluoromethyl-ethoxy)-azetidine-1-carbonyl]-amino}-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-3,6-dihydro-2H-pyridine-1-carboxylic acid dimethylamide,    3-tert-Butoxy-azetidine-1-carboxylic acid {3-[6-(3,6-dihydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-5-fluoro-2-methyl-phenyl}-amide,    4-(4-{3-[(3-tert-Butoxy-azetidine-1-carbonyl)-amino]-4-fluoro-phenyl}-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid dimethylamide,    4-(4-{3-[(3-tert-Butoxy-azetidine-1-carbonyl)-amino]-4-fluoro-2-methyl-phenyl}-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid dimethylamide,    4-tert-Butyl-N-{3-[6-(3,6-dihydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-2-methyl-phenyl}-benzamide,    4-tert-Butyl-N-{3-[6-(1,4-dioxa-spiro[4.5]dec-7-en-8-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-2-methyl-phenyl}-benzamide,    4-tert-Butyl-N-{3-[6-(4-hydroxy-cyclohex-1-enyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-2-methyl-phenyl}-benzamide, and    4-tert-Butyl-N-{3-[6-(4-dimethylamino-cyclohex-1-enyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-2-methyl-phenyl}-benzamide.
As used herein, the term “alkyl” refers to a fully saturated branched or unbranched hydrocarbon moiety having up to 20 carbon atoms. Unless otherwise provided, alkyl refers to hydrocarbon moieties having 1 to 16 carbon atoms, 1 to 10 carbon atoms, 1 to 7 carbon atoms, or 1 to 4 carbon atoms. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, n-decyl and the like.
As used herein, the term “alkenyl” refers to an unsaturated branched or unbranched hydrocarbon moiety having 2 to 20 carbon atoms. It comprises 2 to 20 carbon atoms, Unless otherwise provided, alkenyl refers to moieties having 2 to 16 carbon atoms, 2 to 10 carbon atoms, 2 to 7 carbon atoms, or 2 to 4 carbon atoms. Representative examples of alkenyl include, but are not limited to, ethenyl, n-propenyl, iso-propenyl, n-butenyl, sec-butenyl, iso-butenyl, tert-butenyl, n-pentenyl, isopentenyl, neopentenyl, n-hexenyl, 3-methylhexenyl, 2,2-dimethylpentenyl, 2,3-dimethylpentenyl, n-heptenyl, n-octenyl, n-nonenyl, n-decenyl and the like.
As used herein, the term “alkoxy” refers to alkyl-O—, wherein alkyl is defined herein above. Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, hexyloxy, cyclopropyloxy-, cyclohexyloxy- and the like. Typically, alkoxy groups have about 1-7, more preferably about 1-4 carbons.
As used herein, the term “cycloalkyl” refers to saturated or unsaturated monocyclic, bicyclic or tricyclic hydrocarbon groups of 3-12 carbon atoms. Unless otherwise provided, cycloalkyl refers to cyclic hydrocarbon groups having between 3 and 9 ring carbon atoms or between 3 and 7 ring carbon atoms. Exemplary monocyclic hydrocarbon groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl and cyclohexenyl and the like. Exemplary bicyclic hydrocarbon groups include bornyl, indyl, hexahydroindyl, tetrahydronaphthyl, decahydronaphthyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptenyl, 6,6-dimethylbicyclo[3.1.1]heptyl, 2,6,6-trimethylbicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl and the like. Exemplary tricyclic hydrocarbon groups include adamantyl and the like.
As used herein, the term “azacycloalkane” refers to saturated or unsaturated monocyclic, bicyclic or tricyclic hydrocarbon groups of 3-12 carbon atoms as defined for “cycloalkyl”, wherein one carbon atom is replaced by a nitrogen atom. Unless otherwise provided, azacycloalkyl refers to cyclic aza-hydrocarbon groups having between 2 and 9 ring carbon atoms and one nitrogen atom or between 2 and 7 ring carbon atoms and one nitrogen atom. Exemplary monocyclic aza-hydrocarbon groups include, but are not limited to, aziridinyl, azetidinly, pyrollidinyl, piperidinyl, azepanyl, dihydroazepinyl and the like.
As used herein, the term “halogen” or “halo” refers to fluoro, chloro, bromo, and iodo.
As used herein the term “heterocyclic”, “heterocyclyl” or “heterocyclo” may refer to a saturated or unsaturated non-aromatic ring or ring system, e.g., which is a 4-, 5-, 6-, or 7-membered monocyclic, 7-, 8-, 9-, 10-, 11-, or 12-membered bicyclic or 10-, 11-, 12-, 13-, 14- or 15-membered tricyclic ring system and contains at least one heteroatom selected from O, S and N, where the N and S can also optionally be oxidized to various oxidation states. The heterocyclic group can be attached at a heteroatom or a carbon atom. The heterocyclyl may include fused or bridged rings as well as spirocyclic rings. Examples of heterocycles include azetidine, tetrahydrofuran (THF), dihydrofuran, 1,4-dioxane, morpholine, 1,4-dithiane, piperazine, piperidine, 1,3-dioxolane, imidazolidine, imidazoline, pyrroline, pyrrolidine, tetrahydropyran, dihydropyran, oxathiolane, dithiolane, 1,3-dioxane, 1,3-dithiane, oxathiane, thiomorpholine, and the like.                As used herein, the term “aryloxy” refers to both an —O-aryl and an —O-heteroaryl group, wherein aryl and heteroaryl are defined herein.        As used herein, the term “heteroaryl” refers to a 5-14 membered monocyclic- or bicyclic- or tricyclic-aromatic ring system, having 1 to 8 heteroatoms selected from N, O or S. Typically, the heteroaryl is a 5-10 membered ring system (e.g., 5-7 membered monocycle or an 8-10 membered bicycle) or a 5-7 membered ring system. Typical heteroaryl groups include 2- or 3-thienyl, 2- or 3-furyl, 2- or 3-pyrrolyl, 2-, 4-, or 5-imidazolyl, 3-, 4-, or 5-pyrazolyl, 2-, 4-, or 5-thiazolyl, 3-, 4-, or 5-isothiazolyl, 2-, 4-, or 5-oxazolyl, 3-, 4-, or 5-isoxazolyl, 3- or 5-1,2,4-triazolyl, 4- or 5-1,2,3-triazolyl, tetrazolyl, 2-, 3-, or 4-pyridyl, 3- or 4-pyridazinyl, 3-, 4-, or 5-pyrazinyl, 2-pyrazinyl, and 2-, 4-, or 5-pyrimidinyl.        The term “heteroaryl” also refers to a group in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, where the radical or point of attachment is on the heteroaromatic ring. Nonlimiting examples include 1-, 2-, 3-, 5-, 6-, 7-, or 8-indolizinyl, 1-, 3-, 4-, 5-, 6-, or 7-isoindolyl, 2-, 3-, 4-, 5-, 6-, or 7-indolyl, 2-, 3-, 4-, 5-, 6-, or 7-indazolyl, 2-, 4-, 5-, 6-, 7-, or 8-purinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, or 9-quinolizinyl, 2-, 3-, 4-, 5-, 6-, 7-, or 8-isoquinoliyl, 1-, 3-, 4-, 5-, 6-, 7-, or 8-isoquinoliyl, 1-, 4-, 5-, 6-, 7-, or 8-phthalazinyl, 2-, 3-, 4-, 5-, or 6-naphthyridinyl, 2-, 3-, 5-, 6-, 7-, or 8-quinazolinyl, 3-, 4-, 5-, 6-, 7-, or 8-cinnolinyl, 2-, 4-, 6-, or 7-pteridinyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, or 8-4aH carbazolyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, or 8-carbzaolyl, 1-, 3-, 4-, 5-, 6-, 7-, 8-, or 9-carbolinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9-, or 10-phenanthridinyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, or 9-acridinyl, 1-, 2-, 4-, 5-, 6-, 7-, 8-, or 9-perimidinyl, 2-, 3-, 4-, 5-, 6-, 8-, 9-, or 10-phenathrolinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, or 9-phenazinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9-, or 10-phenothiazinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9-, or 10-phenoxazinyl, 2-, 3-, 4-, 5-, 6-, or I-, 3-, 4-, 5-, 6-, 7-, 8-, 9-, or 10-benzisoqinolinyl, 2-, 3-, 4-, or thieno[2,3-b]furanyl, 2-, 3-, 5-, 6-, 7-, 8-, 9-, 10-, or 11-7H-pyrazino[2,3-c]carbazolyl, 2-, 3-, 5-, 6-, or 7-2H-furo[3,2-b]-pyranyl, 2-, 3-, 4-, 5-, 7-, or 8-5H-pyrido[2,3-d]-o-oxazinyl, 1-, 3-, or 5-1H-pyrazolo[4,3-d]-oxazolyl, 2-, 4-, or 54H-imidazo[4,5-d]thiazolyl, 3-, 5-, or 8-pyrazino[2,3-d]pyridazinyl, 2-, 3-, 5-, or 6-imidazo[2,1-b]thiazolyl, 1-, 3-, 6-, 7-, 8-, or 9-furo[3,4-c]cinnolinyl, 1-, 2-, 3-, 4-, 5-, 6-, 8-, 9-, 10, or 11-4H-pyrido[2,3-c]carbazolyl, 2-, 3-, 6-, or 7-imidazo[1,2-b][1,2,4]triazinyl, 7-benzo[b]thienyl, 2-, 4-, 5-, 6-, or 7-benzoxazolyl, 2-, 4-, 5-, 6-, or 7-benzimidazolyl, 2-, 4-, 4-, 5-, 6-, or 7-benzothiazolyl, 1-, 2-, 4-, 5-, 6-, 7-, 8-, or 9-benzoxapinyl, 2-, 4-, 5-, 6-, 7-, or 8-benzoxazinyl, 1-, 2-, 3-, 5-, 6-, 7-, 8-, 9-, 10-, or 11-1H-pyrrolo[1,2-b][2]benzazapinyl. Typical fused heteroary groups include, but are not limited to 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolinyl, 1-, 3-, 4-, 5-, 6-, 7-, or 8-isoquinolinyl, 2-, 3-, 4-, 5-, 6-, or 7-indolyl, 2-, 3-, 4-, 5-, 6-, or 7-benzo[b]thienyl, 2-, 4-, 5-, 6-, or 7-benzoxazolyl, 2-, 4-, 5-, 6-, or 7-benzimidazolyl, and 2-, 4-, 5-, 6-, or 7-benzothiazolyl.        
As used herein, the terms “salt” or “salts” refers to an acid addition or base addition salt of a compound of the invention. “Salts” include in particular “pharmaceutical acceptable salts”. The term “pharmaceutically acceptable salts” refers to salts that retain the biological effectiveness and properties of the compounds of this invention and, which typically are not biologically or otherwise undesirable. In many cases, the compounds of the present invention are capable of forming acid and/or base salts by virtue of the presence of amino and/or carboxyl groups or groups similar thereto.
Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids, e.g., acetate, aspartate, benzoate, besylate, bromide/hydrobromide, bicarbonate/carbonate, bisulfate/sulfate, camphorsulfonate, chloride/hydrochloride, chlortheophyllonate, citrate, ethandisulfonate, fumarate, gluceptate, gluconate, glucuronate, hippurate, hydroiodide/iodide, isethionate, lactate, lactobionate, laurylsulfate, malate, maleate, malonate, mandelate, mesylate, methylsulphate, naphthoate, napsylate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, polygalacturonate, propionate, stearate, succinate, sulfosalicylate, tartrate, tosylate and trifluoroacetate salts.
Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, sulfosalicylic acid, and the like. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.
Inorganic bases from which salts can be derived include, for example, ammonium salts and metals from columns I to XII of the periodic table. In certain embodiments, the salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper; particularly suitable salts include ammonium, potassium, sodium, calcium and magnesium salts.
Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like. Certain organic amines include isopropylamine, benzathine, cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazine and tromethamine.
The pharmaceutically acceptable salts of the present invention can be synthesized from a basic or acidic moiety, by conventional chemical methods. Generally, such salts can be prepared by reacting free acid forms of these compounds with a stoichiometric amount of the appropriate base (such as Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate or the like), or by reacting free base forms of these compounds with a stoichiometric amount of the appropriate acid. Such reactions are typically carried out in water or in an organic solvent, or in a mixture of the two. Generally, use of non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile is desirable, where practicable. Lists of additional suitable salts can be found, e.g., in “Remington's Pharmaceutical Sciences”, 20th ed., Mack Publishing Company, Easton, Pa., (1985); and in “Handbook of Pharmaceutical Salts: Properties, Selection, and Use” by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).
Any formula given herein is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds. Isotopically labeled compounds have structures depicted by the formulas given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, and chlorine, such as 2H, 3H, 11C, 13C, 14C, 15N, 18F, 31P, 32P, 35S, 36Cl, 125I respectively. The invention includes various isotopically labeled compounds as defined herein, for example those into which radioactive isotopes, such as 3H and 14C, or those into which non-radioactive isotopes, such as 2H and 13C are present. Such isotopically labelled compounds are useful in metabolic studies (with 14C), reaction kinetic studies (with, for example 2H or 3H), detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays, or in radioactive treatment of patients. In particular, an 18F or labeled compound may be particularly desirable for PET or SPECT studies. Isotopically-labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations using an appropriate isotopically-labeled reagents in place of the non-labeled reagent previously employed.
Further, substitution with heavier isotopes, particularly deuterium (i.e., 2H or D) may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements or an improvement in therapeutic index. It is understood that deuterium in this context is regarded as a substituent of a compound of the formula (I). The concentration of such a heavier isotope, specifically deuterium, may be defined by the isotopic enrichment factor. The term “isotopic enrichment factor” as used herein means the ratio between the isotopic abundance and the natural abundance of a specified isotope. If a substituent in a compound of this invention is denoted deuterium, such compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation).
Pharmaceutically acceptable solvates in accordance with the invention include those wherein the solvent of crystallization may be isotopically substituted, e.g. D2O, d6-acetone, d6-DMSO.
Compounds of the invention, i.e. compounds of formula (I) that contain groups capable of acting as donors and/or acceptors for hydrogen bonds may be capable of forming co-crystals with suitable co-crystal formers. These co-crystals may be prepared from compounds of formula (I) by known co-crystal forming procedures. Such procedures include grinding, heating, co-subliming, co-melting, or contacting in solution compounds of formula (I) with the co-crystal former under crystallization conditions and isolating co-crystals thereby formed. Suitable co-crystal formers include those described in WO 2004/078163. Hence the invention further provides co-crystals comprising a compound of formula (I).
As used herein, the term “pharmaceutically acceptable carrier” includes any and all solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (e.g., antibacterial agents, antifungal agents), isotonic agents, absorption delaying agents, salts, preservatives, drug stabilizers, binders, excipients, disintegration agents, lubricants, sweetening agents, flavoring agents, dyes, and the like and combinations thereof, as would be known to those skilled in the art (see, for example, Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, pp. 1289-1329). Except insofar as any conventional carrier is incompatible with the active ingredient, its use in the therapeutic or pharmaceutical compositions is contemplated.
The term “a therapeutically effective amount” of a compound of the present invention refers to an amount of the compound of the present invention that will elicit the biological or medical response of a subject, for example, reduction or inhibition of an enzyme or a protein activity, or ameliorate symptoms, alleviate conditions, slow or delay disease progression, or prevent a disease, etc. In one non-limiting embodiment, the term “a therapeutically effective amount” refers to the amount of the compound of the present invention that, when administered to a subject, is effective to (1) at least partially alleviating, inhibiting, preventing and/or ameliorating a condition, or a disorder or a disease (i) mediated by Btk, or (ii) associated with Btk activity, or (iii) characterized by activity (normal or abnormal) of Btk; or (2) reducing or inhibiting the activity of Btk; or (3) reducing or inhibiting the expression of Btk. In another non-limiting embodiment, the term “a therapeutically effective amount” refers to the amount of the compound of the present invention that, when administered to a cell, or a tissue, or a non-cellular biological material, or a medium, is effective to at least partially reducing or inhibiting the activity of Btk; or reducing or inhibiting the expression of Btk partially or completely.
As used herein, the term “subject” refers to an animal. Typically the animal is a mammal. A subject also refers to for example, primates (e.g., humans, male or female), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds and the like. In certain embodiments, the subject is a primate. In yet other embodiments, the subject is a human.
As used herein, the term “inhibit”, “inhibition” or “inhibiting” refers to the reduction or suppression of a given condition, symptom, or disorder, or disease, or a significant decrease in the baseline activity of a biological activity or process.
As used herein, the term “treat”, “treating” or “treatment” of any disease or disorder refers in one embodiment, to ameliorating the disease or disorder (i.e., slowing or arresting or reducing the development of the disease or at least one of the clinical symptoms thereof). In another embodiment “treat”, “treating” or “treatment” refers to alleviating or ameliorating at least one physical parameter including those which may not be discernible by the patient. In yet another embodiment, “treat”, “treating” or “treatment” refers to modulating the disease or disorder, either physically, (e.g., stabilization of a discernible symptom), physiologically, (e.g., stabilization of a physical parameter), or both. In yet another embodiment, “treat”, “treating” or “treatment” refers to preventing or delaying the onset or development or progression of the disease or disorder.
As used herein, a subject is “in need of” a treatment if such subject would benefit biologically, medically or in quality of life from such treatment.
As used herein, the term “a,” “an,” “the” and similar terms used in the context of the present invention (especially in the context of the claims) are to be construed to cover both the singular and plural unless otherwise indicated herein or clearly contradicted by the context.
All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g. “such as”) provided herein is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention otherwise claimed.
Any asymmetric atom (e.g., carbon or the like) of the compound(s) of the present invention can be present in racemic or enantiomerically enriched, for example the (R)-, (S)- or (R,S)-configuration. In certain embodiments, each asymmetric atom has at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess in the (R)- or (S)-configuration. Substituents at atoms with unsaturated double bonds may, if possible, be present in cis- (Z)- or trans- (E)-form.
Accordingly, as used herein a compound of the present invention can be in the form of one of the possible isomers, rotamers, atropisomers, tautomers or mixtures thereof, for example, as substantially pure geometric (cis or trans) isomers, diastereomers, optical isomers (antipodes), racemates or mixtures thereof.
Any resulting mixtures of isomers can be separated on the basis of the physicochemical differences of the constituents, into the pure or substantially pure geometric or optical isomers, diastereomers, racemates, for example, by chromatography and/or fractional crystallization.
Any resulting racemates of final products or intermediates can be resolved into the optical antipodes by known methods, e.g., by separation of the diastereomeric salts thereof, obtained with an optically active acid or base, and liberating the optically active acidic or basic compound. In particular, a basic moiety may thus be employed to resolve the compounds of the present invention into their optical antipodes, e.g., by fractional crystallization of a salt formed with an optically active acid, e.g., tartaric acid, dibenzoyl tartaric acid, diacetyl tartaric acid, di-O,O′-p-toluoyl tartaric acid, mandelic acid, malic acid or camphor-10-sulfonic acid. Racemic products can also be resolved by chiral chromatography, e.g., high pressure liquid chromatography (HPLC) using a chiral adsorbent.
Furthermore, the compounds of the present invention, including their salts, can also be obtained in the form of their hydrates, or include other solvents used for their crystallization. The compounds of the present invention may inherently or by design form solvates with pharmaceutically acceptable solvents (including water); therefore, it is intended that the invention embrace both solvated and unsolvated forms. The term “solvate” refers to a molecular complex of a compound of the present invention (including pharmaceutically acceptable salts thereof) with one or more solvent molecules. Such solvent molecules are those commonly used in the pharmaceutical art, which are known to be innocuous to the recipient, e.g., water, ethanol, and the like. The term “hydrate” refers to the complex where the solvent molecule is water.
The compounds of the present invention, including salts, hydrates and solvates thereof, may inherently or by design form polymorphs.
In another aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable carrier. The pharmaceutical composition can be formulated for particular routes of administration such as oral administration, parenteral administration, and rectal administration, etc. In addition, the pharmaceutical compositions of the present invention can be made up in a solid form (including without limitation capsules, tablets, pills, granules, powders or suppositories), or in a liquid form (including without limitation solutions, suspensions or emulsions). The pharmaceutical compositions can be subjected to conventional pharmaceutical operations such as sterilization and/or can contain conventional inert diluents, lubricating agents, or buffering agents, as well as adjuvants, such as preservatives, stabilizers, wetting agents, emulsifiers and buffers, etc.
Typically, the pharmaceutical compositions are tablets or gelatin capsules comprising the active ingredient together with                a) diluents, e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine;        b) lubricants, e.g., silica, talcum, stearic acid, its magnesium or calcium salt and/or polyethyleneglycol; for tablets also        c) binders, e.g., magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone; if desired        d) disintegrants, e.g., starches, agar, alginic acid or its sodium salt, or effervescent mixtures; and/or        e) absorbents, colorants, flavors and sweeteners.        
Tablets may be either film coated or enteric coated according to methods known in the art.
Suitable compositions for oral administration include an effective amount of a compound of the invention in the form of tablets, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsion, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use are prepared according to any method known in the art for the manufacture of pharmaceutical compositions and such compositions can contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets may contain the active ingredient in admixture with nontoxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients are, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example, starch, gelatin or acacia; and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets are uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate can be employed. Formulations for oral use can be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example, peanut oil, liquid paraffin or olive oil.
Certain injectable compositions are aqueous isotonic solutions or suspensions, and suppositories are advantageously prepared from fatty emulsions or suspensions. Said compositions may be sterilized and/or contain adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure and/or buffers. In addition, they may also contain other therapeutically valuable substances. Said compositions are prepared according to conventional mixing, granulating or coating methods, respectively, and contain about 0.1-75%, or contain about 1-50%, of the active ingredient.
Suitable compositions for transdermal application include an effective amount of a compound of the invention with a suitable carrier. Carriers suitable for transdermal delivery include absorbable pharmacologically acceptable solvents to assist passage through the skin of the host. For example, transdermal devices are in the form of a bandage comprising a backing member, a reservoir containing the compound optionally with carriers, optionally a rate controlling barrier to deliver the compound of the skin of the host at a controlled and predetermined rate over a prolonged period of time, and means to secure the device to the skin.
Suitable compositions for topical application, e.g., to the skin and eyes, include aqueous solutions, suspensions, ointments, creams, gels or sprayable formulations, e.g., for delivery by aerosol or the like. Such topical delivery systems will in particular be appropriate for dermal application, e.g., for the treatment of skin cancer, e.g., for prophylactic use in sun creams, lotions, sprays and the like. They are thus particularly suited for use in topical, including cosmetic, formulations well-known in the art. Such may contain solubilizers, stabilizers, tonicity enhancing agents, buffers and preservatives.
As used herein a topical application may also pertain to an inhalation or to an intranasal application. They may be conveniently delivered in the form of a dry powder (either alone, as a mixture, for example a dry blend with lactose, or a mixed component particle, for example with phospholipids) from a dry powder inhaler or an aerosol spray presentation from a pressurised container, pump, spray, atomizer or nebuliser, with or without the use of a suitable propellant.
The present invention further provides anhydrous pharmaceutical compositions and dosage forms comprising the compounds of the present invention as active ingredients, since water may facilitate the degradation of certain compounds.
Anhydrous pharmaceutical compositions and dosage forms of the invention can be prepared using anhydrous or low moisture containing ingredients and low moisture or low humidity conditions. An anhydrous pharmaceutical composition may be prepared and stored such that its anhydrous nature is maintained. Accordingly, anhydrous compositions are packaged using materials known to prevent exposure to water such that they can be included in suitable formulary kits. Examples of suitable packaging include, but are not limited to, hermetically sealed foils, plastics, unit dose containers (e. g., vials), blister packs, and strip packs.
The invention further provides pharmaceutical compositions and dosage forms that comprise one or more agents that reduce the rate by which the compound of the present invention as an active ingredient will decompose. Such agents, which are referred to herein as “stabilizers,” include, but are not limited to, antioxidants such as ascorbic acid, pH buffers, or salt buffers, etc.
The compounds of formula I in free form or in salt form, exhibit valuable pharmacological properties, e.g. Btk modulating properties, e.g. as indicated by in vitro and in vivo tests as provided in the next sections and are therefore indicated for therapy.
Compounds of the invention may be useful in the treatment of an indication selected from: Autoimmune disorders, inflammatory diseases, allergic diseases, airway diseases, such as asthma and chronic obstructive pulmonary disease (COPD), transplant rejection; diseases in which antibody production, antigen presentation, cytokine production or lymphoid organogenesis are abnormal or are undesirable; including rheumatoid arthritis, systemic onset juvenile idiopathic arthritis (SOJIA), gout, pemphigus vulgaris, idiopathic thrombocytopenic purpura, systemic lupus erythematosus, multiple sclerosis, myasthenia gravis, Sjögren's syndrome, autoimmune hemolytic anemia, anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitides, cryoglobulinemia, thrombotic thrombocytopenic purpura, chronic autoimmune urticaria, allergy (atopic dermatitis, contact dermatitis, allergic rhinitis), atherosclerosis, type 1 diabetes, type 2 diabetes, inflammatory bowel disease, ulcerative colitis, morbus Crohn, pancreatitis, glomerolunephritis, Goodpasture's syndrome, Hashimoto's thyroiditis, Grave's disease, antibody-mediated transplant rejection (AMR), graft versus host disease, B cell-mediated hyperacute, acute and chronic transplant rejection; thromboembolic disorders, myocardial infarct, angina pectoris, stroke, ischemic disorders, pulmonary embolism; cancers of haematopoietic origin including but not limited to multiple myeloma; leukemia; acute myelogenous leukemia; chronic myelogenous leukemia; lymphocytic leukemia; myeloid leukemia; non-Hodgkin lymphoma; lymphomas; polycythemia vera; essential thrombocythemia; myelofibrosis with myeloid metaplasia; and Waldenstroem disease.
Thus, as a further embodiment, the present invention provides the use of a compound of formula (I) or a salt thereof in therapy. In a further embodiment, the therapy is selected from a disease which may be treated by inhibition of Btk. In another embodiment, the disease is selected from the afore-mentioned list, suitably rheumatoid arthritis, systemic onset juvenile idiopathic arthritis (SOJIA), pemphigus vulgaris, idiopathic thrombocytopenic purpura, systemic lupus erythematosus, multiple sclerosis, myasthenia gravis, Sjögren's syndrome, autoimmune hemolytic anemia, anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitides, cryoglobulinemia, thrombotic thrombocytopenic purpura, chronic autoimmune urticaria, atopic dermatitis, allergic rhinitis, type 1 diabetes, type 2 diabetes, inflammatory bowel disease, morbus Crohn, Goodpasture's syndrome, Grave's disease, antibody-mediated transplant rejection (AMR), B cell-mediated hyperacute, acute and chronic transplant rejection; multiple myeloma; acute myelogenous leukemia; chronic myelogenous leukemia; lymphocytic leukemia; myeloid leukemia; non-Hodgkin lymphoma; myelofibrosis with myeloid metaplasia; and Waldenstroem disease, more suitably rheumatoid arthritis, systemic onset juvenile idiopathic arthritis (SOJIA), systemic lupus erythematosus, multiple sclerosis, Sjögren's syndrome, chronic autoimmune urticaria, atopic dermatitis, allergic rhinitis, type 1 diabetes, type 2 diabetes, inflammatory bowel disease, multiple myeloma; non-Hodgkin lymphoma.
In another embodiment, the invention provides a method of treating a disease which is treated by inhibition of Btk kinase comprising administration of a therapeutically acceptable amount of a compound of formula (I) or a salt thereof. In a further embodiment, the disease is selected from the afore-mentioned list, suitably rheumatoid arthritis, systemic onset juvenile idiopathic arthritis (SOJIA), pemphigus vulgaris, idiopathic thrombocytopenic purpura, systemic lupus erythematosus, multiple sclerosis, myasthenia gravis, Sjögren's syndrome, autoimmune hemolytic anemia, anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitides, cryoglobulinemia, thrombotic thrombocytopenic purpura, chronic autoimmune urticaria, atopic dermatitis, allergic rhinitis, type 1 diabetes, type 2 diabetes, inflammatory bowel disease, morbus Crohn, Goodpasture's syndrome, Grave's disease, antibody-mediated transplant rejection (AMR), B cell-mediated hyperacute, acute and chronic transplant rejection; multiple myeloma; acute myelogenous leukemia; chronic myelogenous leukemia; lymphocytic leukemia; myeloid leukemia; non-Hodgkin lymphoma; myelofibrosis with myeloid metaplasia; and Waldenstroem disease, more suitably rheumatoid arthritis, systemic onset juvenile idiopathic arthritis (SOJIA), systemic lupus erythematosus, multiple sclerosis, Sjögren's syndrome, chronic autoimmune urticaria, atopic dermatitis, allergic rhinitis, type 1 diabetes, type 2 diabetes, inflammatory bowel disease, multiple myeloma; non-Hodgkin lymphoma.
Methods of Synthesizing Pyrrolo-Pyrimidines
Agents of the invention, i.e. compounds in accordance to the definition of formula (I), may be prepared by a reaction sequence (shown below) involving Suzuki coupling of a protected boronic esters II with the corresponding aryl halides I′, conveniently furnishing intermediate III. Deprotection of III, e.g. with diluted hydrochloric acid in methanol or the like and acylation, e.g. with an appropriate acetylating agent, e.g. unsubstituted or substituted acetanhydride in the absence or presence of a solvent, of IV is followed by an additional Suzuki coupling with boronic ester VI and acylation of VII (optionally followed by a deprotection step), as shown in Reaction Scheme 1 below, wherein X denotes N, and the group PG refers to a protecting group such as for example, tert-butyloxycarbonyl, that may be easily removed e.g. by diluted hydrochloric acid in methanol or the like.

Alternatively, the compounds of formula (I) may also be prepared by a reaction sequence involving Suzuki coupling of boronic esters IX with the corresponding aryl halides I′, followed by an additional Suzuki coupling of V with boronic esters VI and an acylation of VII (optionally followed by a deprotection step), as shown in Reaction Scheme 2 below:

Alternatively, the compounds of formula (I) may also be prepared by a reaction sequence involving Suzuki coupling of boronic esters VI with the corresponding aryl halides III, acylation of intermediate X, followed by deprotection of XI and acylation of XII (optionally followed by a deprotection step), as shown in Reaction Scheme 3 below, wherein X denotes N, and the group PG refers to a protecting group that may be easily removed, such as for example, tert-butyloxycarbonyl.

Alternatively, the compounds of formula (I) may also be prepared by a reaction sequence involving Suzuki coupling of boronic esters XIII with the corresponding aryl halides III, followed by deprotection of XI and acylation of XII (optionally followed by a deprotection step), as shown in Reaction Scheme 4 below, wherein X denotes N, and the group PG refers to a protecting group that may be easily removed, such as for example, tert-butyloxycarbonyl.

Alternatively, the compounds of formula (I) may also be prepared by a Suzuki coupling of boronic esters XIV with the corresponding aryl halides III (optionally followed by a deprotection step), as shown in Reaction Scheme 5 below:

Alternatively, the compounds of formula (I) may also be prepared by urea formation reaction of anilines VII (optionally followed by a deprotection step), as shown in Reaction Scheme 6 below:

Alternatively, the compounds of formula (I) may be prepared by a reaction sequence involving Suzuki coupling of boronic esters XIII with the corresponding aryl halides XVI. Protection of XVII is followed by halogenation XVII, deprotection of XIX, and Suzuki coupling of halide XX with boronic ester IX (optionally followed by a deprotection step), as shown in Reaction Scheme 7 below, wherein the group PG refers to a protecting group that may be easily removed, such as for example, benzenesulfonyl.

Synthesis of the Compound(s) of the Invention